Tetracycline Antibiotics Induce Biosynthesis of Pro-Inflammatory Metabolites in the Immunobiotic Bacteroides dorei

The human gut microbiome consists of diverse microbes that communicate through small molecules. Numerous recent studies have demonstrated links between gut microbiota and host physiological processes; however, the underlying metabolites remain elusive in part because laboratory conditions do not replicate the native environment of these bacteria. Herein, we focused on Bacteroides dorei, a predominant and representative member of human gut microbiota, to interrogate the chemical composition and possible biological functions of its secondary metabolome. Using UPLC-MS-guided high-throughput elicitor screening (HiTES), we examined how the metabolome of this commensal bacterium responds to hundreds of FDA-approved drug molecules that the host may intake. We identified low-dose tetracyclines as pleiotropic inducers of the B. dorei secondary metabolome, leading to the identification and structural elucidation of six serine-glycine dipeptide lipids, named doreamides A–F, and two 6-N-acyladenosines. The induced doreamides and N-acyladenosines exhibited pro-inflammatory activities, upregulating tumor necrosis factor α (TNFα), interleukin (IL)-1β, IL-6, and IL-10 in macrophages. Doreamides also triggered production of cathelicidin, which inhibits the growth of multiple bacteria tested but not B. dorei. Our results show that low-dose antibiotics can perturb the secondary metabolome of gut bacteria, and that these induced metabolites can exert immunomodulatory effects and restructure the microbiome.